The purpose of the present study was to develop novel cyclodextrin-containing sublingual formulations of cannabinoids. Complexation of model cannabinoids, Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with randomly methylated beta-cyclodextrin (RM-beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD), were studied by the phase-solubility method. Due to better complexation efficiency, RM-beta-CD was selected for further studies. Solid THC/RM-beta-CD and CBD/RM-beta-CD complexes were prepared by freeze-drying. The dissolutions of both THC and CBD in the presence and absence of RM-beta-CD were determined. THC was selected for in vivo studies: the pharmacokinetics of THC after both sublingual and oral administrations of ethanolic THC and THC/RM-beta-CD complex solutions were studied in rabbits. The aqueous solubility of CBD and THC increased as a function of CD concentration, showing A(L)- and A(P)-type diagrams for HP-beta-CD and RM-beta-CD, respectively. Dissolution rates of THC/RM-beta-CD and CBD/RM-beta-CD complexes were significantly (p < 0.05) higher than those of plain THC and plain CBD, respectively. The absolute bioavailability (F) of THC decreased in the following order: sublingual THC/RM-beta-CD solution (F = 12.1+/-1.4%; mean+/-S.D.; n = 4) > oral THC/RM-beta-CD solution (F = 4.0+/-6.0%) > or = sublingual ethanolic THC solution (F = 3.8+/-2.8%) > oral ethanolic THC solution (F = 1.3+/-1.4%). These results demonstrate that RM-beta-CD increases both the aqueous solubility and dissolution rate of these cannabinoids, making the development of novel sublingual formulation possible. These results also suggest that the sublingual administration of a THC/RM-beta-CD complex substantially increases the bioavailability of THC in rabbits.